Inhibitors of microsomal triglyceride transfer protein and method

Compounds are provided which inhibit microsomal triglyceride transfer protein and thus are useful for lowering serum lipids and treating atherosclerosis and related diseases. The compounds have the structure ##STR1## wherein R.sup.1 to R.sup.6, Q, and X are as defined herein.

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Claims

1. A compound which has the structure ##STR296## where Q is ##STR297## R.sup.1 is a fluorenyl-type group of the structure ##STR298## R.sup.1 is an indenyl-type group of the structure ##STR299## Z.sup.1 and Z.sup.2 are the same or different and are independently a bond, O, S, ##STR300## with the proviso that with respect to B, at least one of Z.sup.1 and Z.sup.2 will be other than a bond; R.sup.11 is alkylene, alkenylene or alkynylene of up to 10 carbon atoms; arylene or mixed arylene-alkylene; R.sup.12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cyclo-alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkyl-alkyl, with the provisos that

(1) when R.sup.12 is H, aryloxy, alkoxy or arylalkoxy, then Z.sup.2 is ##STR301## or a bond and (2) when Z.sup.2 is a bond, R.sup.12 cannot be heteroaryl or heteroarylalkyl;
Z is bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene from 2 to 5 carbon atoms; R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cyclo-heteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy;
R.sup.15a and R.sup.16a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
R.sup.5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl;
R.sup.6 is hydrogen or C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkenyl; all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R.sup.5 set out above; ##STR302## are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; or
an N-oxide ##STR303## thereof; a stereoisomer thereof; or a pharmaceutically acceptable salt thereof.

2. The compound as defined in claim 1 having the formula ##STR304##

3. The compound as defined in claim 1 having the formula ##STR305##

4. The compound as defined in claim 1 wherein R.sup.1 is ##STR306##

5. The compound as defined in claim 4 wherein R.sup.1 is ##STR307## Z is a bond, O or S; R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are each H or one of R.sup.15 and R.sup.16 and one of R.sup.13 and R.sup.14 are halogen;

z.sup.1 is a bond or C.dbd.O;
R.sup.11 is alkylene or alkenylene;
R.sup.12 --Z.sup.2 is ##STR308## R.sup.12a is alkyl, fluorinated lower alkyl or polyfluorinated lower alkyl.

6. The compound as defined in claim 1 wherein R.sup.1 is ##STR309## where R.sup.11 is alkylene or alkenylene; R.sup.12 is H, alkyl, alkenyl, aralkyl, aralkenyl; and R.sup.13 is H or F; and R.sup.15 is H or F; Z is O, S or a bond.

7. The compound as defined in claim 1 wherein R.sup.1 is an indenyl-type group of the structure ##STR310##

8. The compound as defined in claim 1 having the structure ##STR311## where Q is ##STR312## Z is a bond, O or S; where R.sup.5 is cycloalkyl, phenyl, aryl, heteroaryl, or cycloalkyl, phenyl, aryl or heteroaryl, independently substituted at the ortho position with alkyl, alkoxy, haloalkyl (optionally substituted with up to 5 halogens), trifluoro-methyl, aryl, aryloxy, haloalkoxy (optionally substituted with up to 5 halogens), arylalkyl or arylalkoxy;

R.sup.6 is H or CH.sub.3;
R.sup.13 and R.sup.15 are independently H or F;
Z.sup.1 is a bond;
R.sup.11 is alkylene;
R.sup.12 --Z.sup.2 is ##STR313##

9. The compound as defined in claim 8 wherein R.sup.11 is --(CH.sub.2).sub.4 --, Z.sup.1 is a bond, and R.sup.12 --Z.sup.2 is ##STR314##

10. The compound as defined in claim 8 having the structure ##STR315## and R.sup.12 is trifluoromethylalkyl or alkyl.

11. The compound as defined in claim 8 having the structure ##STR316## where R.sup.12 is alkyl.

12. The compound as defined in claim 1 having the structure ##STR317## where Q is ##STR318## where R.sup.5 is cycloalkyl, phenyl, aryl, heteroaryl, or cycloalkyl, phenyl, aryl or heteroaryl, independently substituted at the ortho position with alkyl, alkoxy, haloalkyl (optionally substituted with up to 5 halogens), trifluoromethyl, aryl, aryloxy, haloalkoxy (optionally substituted with up to 5 halogens), arylalkyl or arylalkoxy;

R.sup.6 is H or CH.sub.3;
R.sup.13 and R.sup.15 are independently H or F;
Z.sup.1 is a bond;
R.sup.11 is alkylene;
R.sup.12 --Z.sup.2 is ##STR319## R.sup..sup.12a is alkyl, fluorinated lower alkyl or polyfluorinated lower alkyl,
or Z.sup.2 is a bond and R.sup.12 is alkyl.

14. A method for or treating atherosclerosis, pancreatitis or obesity responsive to a decrease in MTP activity in a patient, which comprises administering to a patient in need of treatment a MTP activity decreasing amount of a compound as defined in claim 1.

15. A method of lowering serum lipid levels, cholesterol and/or triglycerides, or treating hyperlipemia, hyper-lipidemia, hyperlipoproteinemia, hypercholes-terolemia and/or hypertriglyceridemia responsive to a decreasing MTP activity in a patient, which comprises administering to a patient in need of treatment a MTP activity decreasing amount of a compound as defined in claim 1.

Referenced Cited
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Patent History
Patent number: 5885983
Type: Grant
Filed: Apr 23, 1997
Date of Patent: Mar 23, 1999
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)
Inventors: Scott A. Biller (Hopewell, NJ), John K. Dickson, Jr. (Eastampton, NJ)
Primary Examiner: Evelyn Huang
Attorney: Burton Rodney
Application Number: 8/847,775
Classifications
Current U.S. Class: 514/210; 514/2355; Polycyclo Ring System Having A 1,2- Or 1,4-diazine As One Of The Cyclos (514/248); 514/252; Tricyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos (514/290); Plural Ring Nitrogens In The Tricyclo Ring System (514/292); Additional Hetero Ring Attached Directly Or Indirectly To The Quinoline Ring System By Nonionic Bonding (514/314); Ring Nitrogen In The Additional Hetero Ring (e.g., Oxazole, Etc.) (514/340); Bicyclo Ring System Having The Thiazole Ring As One Of The Cyclos (514/367); 1,3-oxazoles (including Hydrogenated) (514/374); 1,2-oxazoles (including Hydrogenated) (514/378); Additional Hetero Ring (514/397); 1,2-diazoles (514/403); Pyrazoles (514/406); Additional Hetero Ring Which Is Not Part Of The Bicyclo Ring System (514/414); The Chalcogen, X, Is In A -c(=x)- Group (548/180); 1,3-oxazoles (including Hydrogenated) (548/215); Having -c(=x)-, Wherein X Is Chalcogen, Bonded Directly To Ring Carbon Of The Oxazole Ring By Nonionic Bonding (548/248); 548/314; 548/3625; 548/3641; Substituent On Ring Carbon Of The Bicyclo Ring System Contains The Additional Hetero Ring (548/467); 548/930; 548/935; The Six-membered Hetero Ring Shares Ring Members With The Five-membered Cyclo Only (e.g., Pyrido-indoles, Etc.) (546/85); The Tricyclo Ring System Consists Of A Five-membered Carbocyclic Ring Ortho Fused To Both A Six-membered Carbocyclic Ring And The Six-membered Hetero Ring (e.g., Indenopyridines, Etc.) (546/111); Having -c(=x)-, Wherein X Is Chalcogen, Bonded Directly To The Six-membered Hetero Ring (546/156); Acyclic Nitrogen Bonded Directly To The -c(=x)- Group (546/169); 546/2681; Oxygen Double Bonded And Acyclic Nitrogen Bonded Directly To The Same Carbon (544/168); Bicyclo Ring System Having The 1,2-diazine Ring As One Of The Cyclos (544/235); 1,2-diazines Which Contain An Additional Hetero Ring (544/238); Nitrogen Attached Directly Or Indirectly To The Purine Ring System By Nonionic Bonding (544/277); Having -c(=x)-, Wherein X Is Chalcogen, Bonded Directly To The Diazine Ring (544/406); Nitrogen Attached Directly To The Diazine Ring By Nonionic Bonding (544/407)
International Classification: A61K 31395; A61K 3141; A61K 31435; A61K 31495; C07D20504;